Abstract
Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 823-838 |
| Number of pages | 16 |
| Journal | American journal of human genetics |
| Volume | 91 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 2 2012 |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. / Asselbergs, Folkert W.; Guo, Yiran; Van Iperen, Erik P.A.; Sivapalaratnam, Suthesh; Tragante, Vinicius; Lanktree, Matthew B.; Lange, Leslie A.; Almoguera, Berta; Appelman, Yolande E.; Barnard, John; Baumert, Jens; Beitelshees, Amber L.; Bhangale, Tushar R.; Chen, Yii Der Ida; Gaunt, Tom R.; Gong, Yan; Hopewell, Jemma C.; Johnson, Toby; Kleber, Marcus E.; Langaee, Taimour Y.; Li, Mingyao; Li, Yun R.; Liu, Kiang; McDonough, Caitrin W.; Meijs, Matthijs F.L.; Middelberg, Rita P.S.; Musunuru, Kiran; Nelson, Christopher P.; O'Connell, Jeffery R.; Padmanabhan, Sandosh; Pankow, James S.; Pankratz, Nathan; Rafelt, Suzanne; Rajagopalan, Ramakrishnan; Romaine, Simon P.R.; Schork, Nicholas J.; Shaffer, Jonathan; Shen, Haiqing; Smith, Erin N.; Tischfield, Sam E.; Van Der Most, Peter J.; Van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Volcik, Kelly A.; Zhang, Li; Bailey, Kent R.; Bailey, Kristian M.; Bauer, Florianne; Boer, Jolanda M.A.; Braund, Peter S.; Burt, Amber; Burton, Paul R.; Buxbaum, Sarah G.; Chen, Wei; Cooper-Dehoff, Rhonda M.; Cupples, L. Adrienne; Dejong, Jonas S.; Delles, Christian; Duggan, David; Fornage, Myriam; Furlong, Clement E.; Glazer, Nicole; Gums, John G.; Hastie, Claire; Holmes, Michael V.; Illig, Thomas; Kirkland, Susan A.; Kivimaki, Mika; Klein, Ronald; Klein, Barbara E.; Kooperberg, Charles; Kottke-Marchant, Kandice; Kumari, Meena; Lacroix, Andrea Z.; Mallela, Laya; Murugesan, Gurunathan; Ordovas, Jose; Ouwehand, Willem H.; Post, Wendy S.; Saxena, Richa; Scharnagl, Hubert; Schreiner, Pamela J.; Shah, Tina; Shields, Denis C.; Shimbo, Daichi; Srinivasan, Sathanur R.; Stolk, Ronald P.; Swerdlow, Daniel I.; Taylor, Herman A.; Topol, Eric J.; Toskala, Elina; Van Pelt, Joost L.; Van Setten, Jessica; Yusuf, Salim; Whittaker, John C.; Zwinderman, A. H.; Anand, Sonia S.; Balmforth, Anthony J.; Berenson, Gerald S.; Bezzina, Connie R.; Boehm, Bernhard O.; Boerwinkle, Eric; Casas, Juan P.; Caulfield, Mark J.; Clarke, Robert; Connell, John M.; Cruickshanks, Karen J.; Davidson, Karina W.; Day, Ian N.M.; De Bakker, Paul I.W.; Doevendans, Pieter A.; Dominiczak, Anna F.; Hall, Alistair S.; Hartman, Catharina A.; Hengstenberg, Christian; Hillege, Hans L.; Hofker, Marten H.; Humphries, Steve E.; Jarvik, Gail P.; Johnson, Julie A.; Kaess, Bernhard M.; Kathiresan, Sekar; Koenig, Wolfgang; Lawlor, Debbie A.; März, Winfried; Melander, Olle; Mitchell, Braxton D.; Montgomery, Grant W.; Munroe, Patricia B.; Murray, Sarah S.; Newhouse, Stephen J.; Onland-Moret, N. Charlotte; Poulter, Neil; Psaty, Bruce; Redline, Susan; Rich, Stephen S.; Rotter, Jerome I.; Schunkert, Heribert; Sever, Peter; Shuldiner, Alan R.; Silverstein, Roy L.; Stanton, Alice; Thorand, Barbara; Trip, Mieke D.; Tsai, Michael Y.; Van Der Harst, Pim; Van Der Schoot, Ellen; Van Der Schouw, Yvonne T.; Verschuren, W. M.Monique; Watkins, Hugh; Wilde, Arthur A.M.; Wolffenbuttel, Bruce H.R.; Whitfield, John B.; Hovingh, G. Kees; Ballantyne, Christie M.; Wijmenga, Cisca; Reilly, Muredach P.; Martin, Nicholas G.; Wilson, James G.; Rader, Daniel J.; Samani, Nilesh J.; Reiner, Alex P.; Hegele, Robert A.; Kastelein, John J.P.; Hingorani, Aroon D.; Talmud, Philippa J.; Hakonarson, Hakon; Elbers, Clara C.; Keating, Brendan J.; Drenos, Fotios.
In: American journal of human genetics, Vol. 91, No. 5, 02.11.2012, p. 823-838.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci
AU - Asselbergs, Folkert W.
AU - Guo, Yiran
AU - Van Iperen, Erik P.A.
AU - Sivapalaratnam, Suthesh
AU - Tragante, Vinicius
AU - Lanktree, Matthew B.
AU - Lange, Leslie A.
AU - Almoguera, Berta
AU - Appelman, Yolande E.
AU - Barnard, John
AU - Baumert, Jens
AU - Beitelshees, Amber L.
AU - Bhangale, Tushar R.
AU - Chen, Yii Der Ida
AU - Gaunt, Tom R.
AU - Gong, Yan
AU - Hopewell, Jemma C.
AU - Johnson, Toby
AU - Kleber, Marcus E.
AU - Langaee, Taimour Y.
AU - Li, Mingyao
AU - Li, Yun R.
AU - Liu, Kiang
AU - McDonough, Caitrin W.
AU - Meijs, Matthijs F.L.
AU - Middelberg, Rita P.S.
AU - Musunuru, Kiran
AU - Nelson, Christopher P.
AU - O'Connell, Jeffery R.
AU - Padmanabhan, Sandosh
AU - Pankow, James S.
AU - Pankratz, Nathan
AU - Rafelt, Suzanne
AU - Rajagopalan, Ramakrishnan
AU - Romaine, Simon P.R.
AU - Schork, Nicholas J.
AU - Shaffer, Jonathan
AU - Shen, Haiqing
AU - Smith, Erin N.
AU - Tischfield, Sam E.
AU - Van Der Most, Peter J.
AU - Van Vliet-Ostaptchouk, Jana V.
AU - Verweij, Niek
AU - Volcik, Kelly A.
AU - Zhang, Li
AU - Bailey, Kent R.
AU - Bailey, Kristian M.
AU - Bauer, Florianne
AU - Boer, Jolanda M.A.
AU - Braund, Peter S.
AU - Burt, Amber
AU - Burton, Paul R.
AU - Buxbaum, Sarah G.
AU - Chen, Wei
AU - Cooper-Dehoff, Rhonda M.
AU - Cupples, L. Adrienne
AU - Dejong, Jonas S.
AU - Delles, Christian
AU - Duggan, David
AU - Fornage, Myriam
AU - Furlong, Clement E.
AU - Glazer, Nicole
AU - Gums, John G.
AU - Hastie, Claire
AU - Holmes, Michael V.
AU - Illig, Thomas
AU - Kirkland, Susan A.
AU - Kivimaki, Mika
AU - Klein, Ronald
AU - Klein, Barbara E.
AU - Kooperberg, Charles
AU - Kottke-Marchant, Kandice
AU - Kumari, Meena
AU - Lacroix, Andrea Z.
AU - Mallela, Laya
AU - Murugesan, Gurunathan
AU - Ordovas, Jose
AU - Ouwehand, Willem H.
AU - Post, Wendy S.
AU - Saxena, Richa
AU - Scharnagl, Hubert
AU - Schreiner, Pamela J.
AU - Shah, Tina
AU - Shields, Denis C.
AU - Shimbo, Daichi
AU - Srinivasan, Sathanur R.
AU - Stolk, Ronald P.
AU - Swerdlow, Daniel I.
AU - Taylor, Herman A.
AU - Topol, Eric J.
AU - Toskala, Elina
AU - Van Pelt, Joost L.
AU - Van Setten, Jessica
AU - Yusuf, Salim
AU - Whittaker, John C.
AU - Zwinderman, A. H.
AU - Anand, Sonia S.
AU - Balmforth, Anthony J.
AU - Berenson, Gerald S.
AU - Bezzina, Connie R.
AU - Boehm, Bernhard O.
AU - Boerwinkle, Eric
AU - Casas, Juan P.
AU - Caulfield, Mark J.
AU - Clarke, Robert
AU - Connell, John M.
AU - Cruickshanks, Karen J.
AU - Davidson, Karina W.
AU - Day, Ian N.M.
AU - De Bakker, Paul I.W.
AU - Doevendans, Pieter A.
AU - Dominiczak, Anna F.
AU - Hall, Alistair S.
AU - Hartman, Catharina A.
AU - Hengstenberg, Christian
AU - Hillege, Hans L.
AU - Hofker, Marten H.
AU - Humphries, Steve E.
AU - Jarvik, Gail P.
AU - Johnson, Julie A.
AU - Kaess, Bernhard M.
AU - Kathiresan, Sekar
AU - Koenig, Wolfgang
AU - Lawlor, Debbie A.
AU - März, Winfried
AU - Melander, Olle
AU - Mitchell, Braxton D.
AU - Montgomery, Grant W.
AU - Munroe, Patricia B.
AU - Murray, Sarah S.
AU - Newhouse, Stephen J.
AU - Onland-Moret, N. Charlotte
AU - Poulter, Neil
AU - Psaty, Bruce
AU - Redline, Susan
AU - Rich, Stephen S.
AU - Rotter, Jerome I.
AU - Schunkert, Heribert
AU - Sever, Peter
AU - Shuldiner, Alan R.
AU - Silverstein, Roy L.
AU - Stanton, Alice
AU - Thorand, Barbara
AU - Trip, Mieke D.
AU - Tsai, Michael Y.
AU - Van Der Harst, Pim
AU - Van Der Schoot, Ellen
AU - Van Der Schouw, Yvonne T.
AU - Verschuren, W. M.Monique
AU - Watkins, Hugh
AU - Wilde, Arthur A.M.
AU - Wolffenbuttel, Bruce H.R.
AU - Whitfield, John B.
AU - Hovingh, G. Kees
AU - Ballantyne, Christie M.
AU - Wijmenga, Cisca
AU - Reilly, Muredach P.
AU - Martin, Nicholas G.
AU - Wilson, James G.
AU - Rader, Daniel J.
AU - Samani, Nilesh J.
AU - Reiner, Alex P.
AU - Hegele, Robert A.
AU - Kastelein, John J.P.
AU - Hingorani, Aroon D.
AU - Talmud, Philippa J.
AU - Hakonarson, Hakon
AU - Elbers, Clara C.
AU - Keating, Brendan J.
AU - Drenos, Fotios
PY - 2012/11/2
Y1 - 2012/11/2
N2 - Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
AB - Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
UR - http://www.scopus.com/inward/record.url?scp=84868470681&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868470681&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.08.032
DO - 10.1016/j.ajhg.2012.08.032
M3 - Article
C2 - 23063622
AN - SCOPUS:84868470681
VL - 91
SP - 823
EP - 838
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -